Novel osteogenic peptide from bovine bone collagen hydrolysate: Targeted screening, molecular mechanism, and stability analysis.

This study aimed to screen for a novel osteogenic peptide based on the calcium-sensing receptor (CaSR) and explore its molecular mechanism and gastrointestinal stability. In this study, a novel osteogenic peptide (Phe-Ser-Gly-Leu, FSGL) derived from bovine bone collagen hydrolysate was successfully screened by molecular docking and synthesised by solid phase peptide synthesis for further analysis. Cell experiments showed that FSGL significantly enhanced the osteogenic activity of MC3T3-E1 cells by acting on CaSR, including proliferation (152.53%), differentiation, and mineralization. Molecular docking and molecular dynamics further demonstrated that FSGL was a potential allosteric activator of CaSR, that turned on the activation switch of CaSR by closing the Venus flytrap (VFT) domain and driving the two protein chains in the VFT domain to easily form dimers. In addition, 96.03% of the novel osteogenic peptide FSGL was stable during gastrointestinal digestion. Therefore, FSGL showed substantial potential for enhancing the osteogenic activity of osteoblasts. This study provided new insights for the application of CaSR in the targeted screening of osteogenic peptides to improve bone health.

Synergistic Effects of Shed-Derived Exosomes, Cu2+, and an Injectable Hyaluronic Acid Hydrogel on Antibacterial, Anti-inflammatory, and Osteogenic Activity for Periodontal Bone Regeneration.

The primary pathology of periodontitis involves the gradual deterioration of periodontal tissues resulting from the inflammatory reaction triggered by bacterial infection. In this study, a novel drug for periodontal pocket injection, known as the Shed-Cu-HA hydrogel, was developed by incorporating copper ions (Cu2+) and Shed-derived exosomes (Shed-exo) inside the hyaluronic acid (HA) hydrogel. Suitable concentrations of Cu2+ and Shed-exo released from Shed-Cu-HA enhanced cell viability and cell proliferation of human periodontal ligament stem cells. Additionally, the Shed-Cu-HA demonstrated remarkable antibacterial effects against the key periodontal pathogen (Aa) owing to the synergistic effect of Cu2+ and HA. Furthermore, the material effectively suppressed macrophage inflammatory response via the IL-6/JAK2/STAT3 pathway. Moreover, the Shed-Cu-HA, combining the inflammation-regulating properties of HA with the synergistic osteogenic activity of Shed-exo and Cu2+, effectively upregulated the expression of genes and proteins associated with osteogenic differentiation. The experimental findings from a mouse periodontitis model demonstrated that the administration of Shed-Cu-HA effectively reduced the extent of inflammatory cell infiltration and bacterial infections in gingival tissues and facilitated the regeneration of periodontal bone tissues and collagen after 2 and 4 weeks of injection. Consequently, it holds significant prospects for future applications in periodontitis treatment.

Functionalized BP@(Zn+Ag)/EPLA Nanofibrous Scaffolds Fabricated by Cryogenic 3D Printing for Bone Tissue Engineering.

This study fabricates a functionalized scaffold by cryogenic three-dimensional (3D) printing using an aminated poly-L-lactic acid (EPLA) solution containing nanosilver/zinc-coated black phosphorus (BP@(Zn+Ag)) nanocomposites. The nanocomposites are prepared by a green method of in situ photodeposition of silver and zinc nanoparticles (AgNPs and ZnNPs) on BP nanosheets (BPNs) under visible light irradiation without any chemical reductant. Scanning electron microscope (SEM) and X-ray energy dispersive spectrometer (EDS) confirm the uniform distribution of BP@(Zn+Ag) nanoparticles in the EPLA nanofibrous matrix. The in vitro tests show that the fabricated BP@(Zn+Ag)/EPLA nanofibrous scaffold exhibits excellent antibacterial activity (over 96%) against E. coli and S. aureus, as well as enhanced cell viability and osteogenic activity to facilitate the growth and differentiation of osteoblasts. The in vivo rat calvarial defect model also demonstrates that the BP@(Zn+Ag)/EPLA nanofibrous scaffold promotes new bone tissue formation around the implant site. Therefore, the prepared multifunctional 3D printed BP@(Zn+Ag)/EPLA nanofibrous scaffold has great potential for bone tissue engineering (BTE) applications.

The screened compounds from Ligustri Lucidi Fructus using the immobilized calcium sensing receptor column exhibit osteogenic activity in vitro.

Calcium sensing receptor (CaSR) has become the novel target of treating osteoporosis with herbal medicine Ligustri Lucidi Fructus (LLF), however, the bioactive compounds responsible for anti-osteoporosis are hard to clarify due to the complexity and diversity of chemical constituents in it. Herein, the immobilized CaSR column was packed with stationary phase materials, which were derived from integrating CLIP-tagged CaSR directly out of crude cell lysates onto the surface of silica gels (5.83 mg/g) in a site-specific covalent manner. The column had a great specificity of recognizing agonists and kept a good stability for at least 3 weeks. The two compounds from LLF extract were screened and identified as olenuezhenoside and ligustroflavone using the immobilized CaSR column in conjunction with mass spectrometry. Molecular docking predicted that both compounds were bound in venus flytrap (VFT) domain of CaSR by the formation of hydrogen bonds. Cellular results showed that both compounds exhibited the distinct osteogenic activity by enhancing the proliferation, differentiation and mineralization of osteoblastic cells. Our study demonstrated that, the immobilized protein column enables to screen the bioactive compounds rapidly from herbal extract, and the newly discovered natural product ligands towards CaSR, including olenuezhenoside and ligustroflavone, will be the candidates for the treatment of osteoporosis.

Regulating the bioactivity of non-glycosylated recombinant human bone morphogenetic protein-2 to enhance bone regeneration.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is the predominant growth factor that effectively induces osteogenic differentiation in orthopedic procedures. However, the bioactivity and stability of rhBMP-2 are intrinsically associated with its sequence, structure, and storage conditions. In this study, we successfully determined the amino acid sequence and protein secondary structure model of non-glycosylated rhBMP-2 expressed by an E. coli expression system through X-ray crystal structure analysis. Furthermore, we observed that acidic storage conditions enhanced the proliferative and osteoinductive activity of rhBMP-2. Although the osteogenic activity of non-glycosylated rhBMP-2 is relatively weaker compared to glycosylated rhBMP-2; however, this discrepancy can be mitigated by incorporating exogenous chaperone molecules. Overall, such information is crucial for rationalizing the design of stabilization methods and enhancing the bioactivity of rhBMP-2, which may also be applicable to other growth factors.

A Zn2+ cross-linked sodium alginate/epigallocatechin gallate hydrogel scaffold for promoting skull repair.

The optimal material for repairing skull defects should exhibit outstanding biocompatibility and mechanical properties. Specifically, hydrogel scaffolds that emulate the microenvironment of the native bone extracellular matrix play a vital role in promoting osteoblast adhesion, proliferation, and differentiation, thereby yielding superior outcomes in skull reconstruction. In this study, a composite network hydrogel comprising sodium alginate (SA), epigallocatechin gallate (EGCG), and zinc ions (Zn2+) was developed to establish an ideal osteogenic microenvironment for bone regeneration. Initially, physical entanglement and hydrogen bonding between SA and EGCG resulted in the formation of a primary network hydrogel known as SA-EGCG. Subsequently, the inclusion of Zn2+ facilitated the creation of a composite network hydrogels named SA-EGCG-Zn2+ via dynamic coordination bonds with SA and EGCG. The engineered SA-EGCG2 %-Zn2+ hydrogels offered an environment mimicking the native extracellular matrix (ECM). Moreover, the sustained release of Zn2+ from the hydrogel effectively enhanced cell adhesion, promoted proliferation, and stimulated osteoblast differentiation. In vitro experiments have shown that SA-EGCG2 %-Zn2+ hydrogels greatly enhance the attachment and growth of osteoblast precursor cells (MC3T3-E1), while also increasing the expression of genes related to osteogenesis in these cells. Additionally, in vivo studies have confirmed that SA-EGCG2 %-Zn2+ hydrogels promote new bone formation and accelerate the regeneration of bone in situ, indicating promising applications in the realm of bone tissue engineering.

Injectable and In Situ Formed Dual-Network Hydrogel Reinforced by Mesoporous Silica Nanoparticles and Loaded with BMP-4 for the Closure and Repair of Skull Defects.

Bone defects are a common and challenging orthopedic problem with poor self-healing ability and long treatment cycles. The difficult-to-heal bone defects cause a significant burden of medical expenses on patients. Currently, biomaterials with mechanical stability, long-lasting action, and osteogenic activity are considered as a suitable way to effectively heal bone defects. Here, an injectable double network (DN) hydrogel prepared using physical and chemical cross-linking methods is designed. The first rigid network is constructed using methylpropenylated hyaluronic acid (HAMA), while the addition of chitosan oligosaccharide (COS) forms a second flexible network by physical cross-linking. The mesoporous silica nanoparticles (MSN) loaded with bone morphogenetic protein-4 (BMP-4) were embedded into DN hydrogel, which not only enhanced the mechanical stability of the hydrogel, but also slowly released BMP-4 to achieve long-term skull repair. The designed composite hydrogel showed an excellent compression property and deformation resistance. In vitro studies confirmed that the HAMA/COS/MSN@BMP-4 hydrogel had good biocompatibility and showed great potential in supporting proliferation and osteogenic differentiation of mouse embryo osteoblast precursor (MC3T3-E1) cells. Furthermore, in vivo studies confirmed that the DN hydrogel successfully filled and closed irregular skull defect wounds, effectively promoted bone regeneration, and significantly promoted bone repair compared with the control group. In addition, HAMA/COS/MSN@BMP-4 hydrogel precursor solution can quickly form hydrogel in situ at the wound by ultraviolet light, which can be applied to the closure and repair of wounds of different shapes, which provides the new way for the treatment of bone defects.

Ag2 O-TiO2 -NTs enhance osteogenic activity in vitro by modulating TNF-α/ß-catenin signaling in bone marrow-derived mesenchymal stem cells.

The toxic effects of nanoparticles-silver oxide (Ag2 O) limited its use. However, loading Ag2 O nanoparticles into titanium dioxide (TiO2 ) nanotubes (Ag2 O-TiO2 -NTs) has more efficient biological activity and safety. The aim of this study was to observe the effect of Ag2 O-TiO2 -NTs on osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and its mechanism. The enzyme activity of lactate dehydrogenase (LDH) and the expression of RUNX family transcription factor 2 (Runx2), OPN, OCN in BMSCs were detected by quantitative real time polymerase chain reaction. At 14 days of induction, the mineralization ability and alkaline phosphatase (ALP) activity of cells in each group were observed by Alizarin Red S staining and ALP staining. In addition, the protein levels of tumor necrosis factor-α (TNF-α) and ß-catenin in BMSCs of each group were observed by western blot. After 14 days of the induction, the mineralization ability and ALP activity of BMSCs in the Ag2 O-TiO2 -NTs group were significantly enhanced compared with those in the Ag2 O and TiO2 groups. Western blot analysis showed that the BMSCs in the Ag2 O-TiO2 -NTs group exhibited much lower protein level of TNF-α and higher protein level of ß-catenin than those in the Ag2 O and TiO2 groups.Ag2 O-TiO2 -NTs enhance the osteogenic activity of BMSCs by modulating TNF-α/ß-catenin signaling.

Synergistic Effect of Nano Strontium Titanate Coating and Ultraviolet C Photofunctionalization on Osteogenic Performance and Soft Tissue Sealing of poly(ether-ether-ketone).

This study aimed to evaluate the bioactivity of poly(ether ether ketone) (PEEK) after surface modification by persistent photoconductive strontium titanate (SrTiO3) magnetron sputtering and ultraviolet (UV) C irradiation. According to the different modifications, the PEEK specimens were randomly divided into five groups (n = 38/group): PEEK, Sr100-PEEK, Sr200-PEEK, UV/PEEK, and UV/Sr200-PEEK. Then, the specimens of Sr100-PEEK and Sr200-PEEK groups were, respectively, coated with 100 and 200 nm thickness photocatalyst SrTiO3 on the PEEK surface by magnetron sputtering. Subsequently, UV-C light photofunctionalized the specimens of PEEK and Sr200-PEEK groups to form UV/PEEK and UV/Sr200-PEEK groups. The specimens were characterized by a step meter, scanning electron microscopy (SEM), atomic force microscopy (AFM), energy dispersive X-ray spectroscopy (EDX), and a water contact angle meter. The release test of the Sr ion was performed by inductively coupled plasma mass spectrometry (ICP-MS). In vitro study, osteogenic activity (MC3T3-E1 osteoblast-like cells) and epithelial and connective tissue attachment (gingival epithelial cells GE1 and fibroblasts NIH3T3) were analyzed in five groups. Surface morphology of the specimens was changed after coating, and the Sr content on the Sr-PEEK surface was increased with increasing coating thickness. In addition, the contact angle was increased significantly after magnetron sputtering. After UV-C photofunctionalization, the content of surface elements changed and the contact angle was decreased. The release of Sr ion was sustained, and the final cumulative release amount did not exceed the safety limit. In vitro experiments showed that SrTiO3 improved the cell activity of MC3T3-E1 and UV-C irradiation further enhanced the osteogenic performance of PEEK. Besides, UV-C irradiation also significantly promoted the cell viability, development, and expression of adhesion proteins of GE1 and NIH3T3 on PEEK. The present investigation demonstrated that nano SrTiO3 coating with UV-C photofunctionalization synergistically enhanced the osteogenic properties and soft tissue sealing function of PEEK in vitro.

Stimulation of Osteogenic Activity of Autologous Teeth Hard Tissues as Bone Augmentation Material.

The issue of bone volume loss is playing an increasing role in bone tissue engineering. Research has focused on studying the preparation and use of different types of human or xenogenic materials and their osteogenic properties. An alternative source for this purpose could be autologous extracted teeth. The simple preparation protocol, minimal immune response, and rapid organizing of the newly formed bone with optimal mechanical properties predispose autologous hard teeth tissues (HTTs) as a promising material suitable in the indication of augmentation of maxillary and mandible defects, comparable to other high-end augmentation materials. The aim of this study was to experimentally evaluate the osteogenic potential of ground native autologous HTTs prepared by different demineralization procedures, aimed at potentiating the osteoinductive and osteoconductive properties of their organic components. The results indicate that the most effective preparation process for HTT stimulation is the application of Cleanser for 10 min followed by exposure to 0.6 N HCl for 5 min with a wash in phosphate-buffered saline solution.

Application of metal ions in bone tissue engineering / 中国组织工程研究

BACKGROUND:Metal ions play an important role in the human body.With the progress of material synthesis and processing technology,a variety of metal ions that can be used in bone tissue engineering have been developed,such as magnesium(Mg2+),zinc(Zn2+),manganese(Mn2+),strontium(Sr2+),and copper(Cu2+). OBJECTIVE:To summarize the research progress and development direction of metal ions in bone tissue engineering. METHODS:The literature collected by CNKI,PubMed and WanFang databases from 2014 to 2022 was retrieved.The Chinese and English key words were"metal ions,bone tissue engineering,osteogenic activity,magnesium ions,zinc ions,manganese ions,strontium ions,copper ions,calcium ions,lithium ions,cobalt ions". RESULTS AND CONCLUSION:Different metal ions will be released to varying degrees after the materials are implanted into the body,which can change the tissue microenvironment,thus improving the ability of materials to form blood vessels and bones.Compared with growth factors,metal ions are easier to control the release rate,have lower cost,and can also improve the mechanical properties of implant materials.The application of metal ions in bone tissue engineering is full of prospects.Although some metal ions can already be used to treat bone defects,the mechanism of action of many metal ions in the human body is not completely clear,and the application effect is a lack of clinical experiment verification.Further exploration is needed before clinical application.

3D printing of MOF-reinforced methacrylated gelatin scaffolds for bone regeneration.

Scaffolds based on gelatin (Gel) play a crucial role in bone tissue engineering. However, the low mechanical properties, rapid biodegradation rate, insufficient osteogenic activity and lacking anti-infective properties limit their applications in bone regeneration. Herein, the incorporation of ibuprofen (IBU)-loaded zeolitic imidazolate framework-8 (ZIF-8) in a methacrylated gelatin (GelMA) matrix was proposed as a simple and effective strategy to develop the IBU-ZIF-8@GelMA scaffolds for enhanced bone regeneration capacity. Results indicated that the IBU-loaded ZIF-8 nanoparticles with tiny particle sizes were uniformly distributed in the GelMA matrix of the IBU-ZIF-8@GelMA scaffolds, and the IBU-loaded ZIF-8 growing in the scaffolds enabled the controlled and sustained releasing of Zn2+ and IBU in pH = 5.5 over a long period for efficient bone repair and long-term anti-inflammatory activity. Furthermore, the doping of the IBU-loaded ZIF-8 nanoparticles efficiently enhanced the compression performance of the GelMA scaffolds. In vitro studies indicated that the prepared scaffolds presented no cytotoxicity to MC3T3-E1 cells and the released Zn2+ during the degradation of the scaffolds promoted MC3T3-E1 cell osteogenic differentiation. Thus, the drug-loaded ZIF-8 modified 3D printed GelMA scaffolds demonstrated great potential in treating bone defects.

Novel Calcium-Binding Peptide from Bovine Bone Collagen Hydrolysates and Its Potential Pro-Osteogenic Activity via Calcium-Sensing Receptor (CaSR).

SCOPE: This paper aims to explore the osteogenic activity and potential mechanism of the peptide-calcium chelate, and provides a theoretical basis for peptide-calcium chelates as functional foods to prevent or improve osteoporosis. METHODS AND RESULTS: In this research, a novel peptide (Phe-Gly-Leu, FGL) with a high calcium-binding capacity is screened from bovine bone collagen hydrolysates (CPs), calcium binding sites of which mainly included carbonyl, amino and carboxyl groups. The FGL-Ca significantly enhances the osteogenic activity of MC3T3-E1 cells (survival rate, differentiation, and mineralization). The results of calcium fluorescence labeling and molecular docking show that FGL-Ca may activate calcium-sensing receptor (CaSR), leading to an increase in intracellular calcium concentration, then enhancing osteogenic activity of MC3T3-E1 cells. Further research found that FGL-Ca significantly promotes the mRNA and protein expression levels of CaSR, transforming growth factor ß (TGF-ß1), TGF-ß-type II receptor (TßRII), Smad2, Smad3, osteocalcin (OCN), alkaline phosphatase (ALP), osteoprotegrin (OPG), and collagen type I (COLI). Subsequently, in the signal pathway intervention experiment, the expression levels of genes and proteins related to the TGF-ß1/Smad2/3 signaling pathway that are promoted by FGL-Ca are found to decrease. CONCLUSIONS: These results suggest that FGL-Ca may activate CaSR, increase intracellular calcium concentration, and activate TGF-ß1/Smad2/3 signaling pathway, which may be one of the potential mechanisms for enhancing osteogenic activity.

Long-Term Temporospatial Complementary Relationship between Degradation and Bone Regeneration of Mg-Al Alloy.

The utilization of guided tissue regeneration membranes is a significant approach for enhancing bone tissue growth in areas with bone defects. Biodegradable magnesium alloys are increasingly being used as guided tissue regeneration membranes due to their outstanding osteogenic properties. However, the degradation rates of magnesium alloy bone implants documented in the literature tend to be rapid. Moreover, many studies focus only on the initial 3-month period post-implantation, limiting their applicability and impeding clinical adoption. Furthermore, scant attention has been given to the interplay between the degradation of magnesium alloy implants and the adjacent tissues. To address these gaps, this study employs a well-studied magnesium-aluminum (Mg-Al) alloy membrane with a slow degradation rate. This membrane is implanted into rat skull bone defects and monitored over an extended period of up to 48 weeks. Observations are conducted at various intervals (2, 4, 8, 12, 24, and 48 weeks) following the implantation. Assessment of degradation behavior and tissue regeneration response is carried out using histological sections, micro-CT scans, and scanning electron microscopy (SEM). The findings reveal that the magnesium alloy membranes demonstrate remarkable biocompatibility and osteogenic capability over the entire observation duration. Specifically, the Mg-Al alloy membranes sustain their structural integrity for 8 weeks. Notably, their osteogenic ability is further enhanced as a corrosion product layer forms during the later stages of implantation. Additionally, our in vitro experiments employing extracts from the magnesium alloy display a significant osteogenic effect, accompanied by a notable increase in the expression of osteogenic-related genes. Collectively, these results strongly indicate the substantial potential of Mg-Al alloy membranes in the context of guided tissue regeneration.

Highly anisotropic and elastic cellulosic scaffold guiding cell orientation and osteogenic differentiation via topological and mechanical cues.

Inspired by the similarity of anisotropic channels in wood to the canals of bone, the elastic wood-derived (EW) scaffolds with anisotropic channels were prepared via simple delignification treatment of natural wood (NW). We hypothesize that the degree of delignification will lead to differences in mechanical properties of scaffolds, which in turn directly affect the behaviors and fate of stem cells. The delignification process did not destroy the anisotropic channel structure of the scaffolds, but endowed the scaffolds with good elasticity and rapid stress relaxation. Interestingly, the micron-scale anisotropic channels of the scaffolds can highly promote the polarization of cells along the direction of channels. We also found that the alkaline phosphatase of EW scaffold can reach to about 13.1 U/gprot, which was about double that of NW scaffold. Moreover, the longer the delignification time, the better the osteogenic activity of the EW scaffolds. We further hypothesize that the osteogenic activity of scaffolds is related to the stress relaxation properties. The immunofluorescence staining showed that when the stress relaxation time of scaffold was shortened to about 10 s, the nuclear ratio of YAP of scaffold increased to 0.22, which well supports our hypothesis.

Robust Osteoconductive ß-Tricalcium Phosphate/L-poly(lactic acid) Membrane via Orientation-Strengthening Technology.

L-poly(lactic acid) (PLLA) is a biodegradable material with multiple biomedical application potentials, especially as a membrane for guided bone regeneration. In terms of its low strength and poor osteogenic activity, improving these two properties is the key to resolve the limitations of PLLA for bone-associated applications. Herein, an orientation-strengthening technology (OST) was developed to reinforce PLLA's mechanical strength by introducing biocompatible ß-tricalcium phosphate (ß-TCP) to improve the crystallinity of PLLA, allowing for the formation of a highly oriented architecture to acquire an advanced membrane with high mechanical property. Furthermore, the addition of ß-TCP nanoparticles significantly promotes the osteogenic activity of the composites. The tensile strength of the membrane containing 5 wt % ß-TCP was 220 MPa, which was 4-folds that of the native polylactic acid fabricated via the conventional method. The oriented microstructure enhanced both the mechanical strength and the osteogenic activity of the material. The parallel grooves on the material surface are similar to the mineralized collagen fibers on the bone surface, which promoted the growth and differentiation of osteoblasts, with ß-TCP further contributing to the osteoconductive effect. The combination of ß-TCP and orientation-strengthening effect endows the material with higher mechanical properties and bioactivities, which provides an advanced manufacturing strategy for the preparation of PLLA-based materials for bone repair.

Varying degrees of spontaneous osteogenesis of Masquelet's induced membrane: experimental and clinical observations.

BACKGROUND: Masquelet's induced membrane (IM) has osteogenesis activity, but IM spontaneous osteogenesis (SO) has not been described previously. OBJECTIVES: To report on varying degrees of IMSO and analyze its possible causes. METHODS: Twelve eight-week-old male Sprague-Dawley rats with 10 mm right femoral bone defects who received the first stage of IM technique (IMT) were used to observe the SO. In addition, clinical data from patients with bone defects who received the first stage of IMT with an interval of > 2 months post-operatively and exhibited SO between January 2012 and June 2020 were retrospectively analyzed. The SO was divided into four grades according to the amount and characteristics of the new bone formation. RESULTS: At twelve weeks, grade II SO was observed in all rats, and more new bone was formed in the IM near the bone end forming an uneven margin. Histology revealed bone and cartilage foci in the new bone. Four of the 98 patients treated with the first stage of IMT exhibited IMSO, including one female and three males with a median age of 40.5 years (range 29-52 years). The bone defects were caused by severe fractures and infection in two cases and by infection or tumor in one case each. Partial or segmental defects occurred in two cases. The time interval between inserting a cement spacer and diagnosis of SO ranged from six months to nine years. Two cases were grade I, and one case each of grades III and IV. CONCLUSION: Varying degrees of SO confirm the existence of the IMSO phenomenon. Bioactive bone tissue or local inflammation and a long time interval are the primary reasons underlying enhancement of the osteogenic activity of IM and leading to SO, which tends to take place as endochondral osteogenesis.

Surface Modification of Titanium Implants by Metal Ions and Nanoparticles for Biomedical Application.

Implant surface modification can improve osseointegration and reduce peri-implant inflammation. Implant surfaces are modified with metals because of their excellent mechanical properties and significant functions. Metal surface modification is divided into metal ions and nanoparticle surface modification. These two methods function by adding a finishing metal to the surface of the implant, and both play a role in promoting osteogenic, angiogenic, and antibacterial properties. Based on this, the nanostructural surface changes confer stronger antibacterial and cellular affinity to the implant surface. The current paper reviews the forms, mechanisms, and applications of nanoparticles and metal ion modifications to provide a foundation for the surface modification of implants.

Incorporation of synthetic water-soluble curcumin polymeric drug within calcium phosphate cements for bone defect repairing.

Modified macroporous structures and active osteogenic substances are necessary to overcome the limited bone regeneration capacity and low degradability of self-curing calcium phosphate cement (CPC). Curcumin (CUR), which possesses strong osteogenic activity and poor aqueous solubility/bioavailability, esterifies the side chains in hyaluronic acid (HA) to form a water-soluble CUR-HA macromolecule. In this study, we incorporated the CUR-HA and glucose microparticles (GMPs) into the CPC powder to fabricate the CUR-HA/GMP/CPC composite, which not only retained the good injectability and mechanical strength of bone cements, but also significantly increased the cement porosity and sustained release property of CUR-HA in vitro. CUR-HA incorporation greatly improved the differentiation ability of bone marrow mesenchymal stem cells (BMSCs) to osteoblasts by activating the RUNX family transcription factor 2/fibroblast growth factor 18 (RUNX2/FGF18) signaling pathway, increasing the expression of osteocalcin and enhancing the alkaline phosphatase activity. In addition, in vivo implantation of CUR-HA/GMP/CPC into femoral condyle defects dramatically accelerated the degradation rate of cement and boosted local vascularization and osteopontin protein expression, and consequently promoted rapid bone regeneration. Therefore, macroporous CPC based composite cement with CUR-HA shows a remarkable ability to repair bone defects and is a promising translational application of modified CPC in clinical practice.

A surface metal ion-modified 3D-printed Ti-6Al-4V implant with direct and immunoregulatory antibacterial and osteogenic activity.

The high concentration of antibacterial metal ions may exhibit unavoidable toxicity to cells and normal tissues. The application of antibacterial metal ions to activate the immune response and induce macrophages to attack and phagocytose bacteria is a new antimicrobial strategy. Herein, 3D-printed Ti-6Al-4V implants modified by copper, and strontium ions combined with natural polymers were designed to treat implant-related infections and osseointegration disorders. The polymer-modified scaffolds rapidly released a large amount of copper and strontium ions. During the release process, copper ions were employed to promote the polarization of M1 macrophages, thus inducing a proinflammatory immune response to inhibit infection and achieve the immune antibacterial activity. Meanwhile, copper and strontium ions promoted the secretion of bone-promoting factors by macrophages, induced osteogenesis and showed immunomodulatory osteogenesis. This study proposed immunomodulatory strategies based on the immunological characteristics of target diseases and provided ideas for the design and synthesis of new immunoregulatory biomaterials.